Randomized trial finds carotid endarterectomy or stenting not superior to best medical therapy in asymptomatic patients

Five-year results from a multicenter randomized controlled trial (RCT) indicate that carotid endarterectomy (CEA) or carotid stenting (CAS) for moderate to severe asymptomatic carotid stenosis is not superior to best medical therapy (BMT) alone.

Tilman Reiff (University Hospital Heidelberg, Heidelberg, Germany) and colleagues recently reported this important conclusion from the SPACE-2 study in The Lancet Neurology. The authors claim that, to the best of their knowledge, this is the first randomized trial directly comparing CEA plus BMT, CAS plus BMT, and BMT alone over a five-year period in patients with asymptomatic carotid stenosis.

“The optimal treatment for patients with asymptomatic CAS is debated,” the researchers write, noting that the benefit of CEA or CAS is “unclear” given that BMT has improved over time. They add that randomized data comparing the effect of CEA and CAS versus BMT alone are lacking, and therefore aimed to directly compare CEA plus BMT to CAS plus BMT and both to BMT in the SPACE-2 study only.

SPACE-2 was a multicenter RCT conducted at 36 study centers in Austria, Germany and Switzerland, Reiff et al details in their report. Researchers recruited participants aged 50-85 years with asymptomatic carotid stenosis of the distal carotid artery or extracranial internal carotid artery of at least 70% according to European Carotid Surgery Trial criteria (equivalent to at least 50-99% according to North American symptomatic carotid artery -Endarterectomy study [NASCET] Criteria).

Reiff and colleagues point out that SPACE-2 was originally designed as a three-arm study with a BMT-only group. However, due to slow recruitment, the design was changed to become two sub-studies, each with two arms, comparing CEA plus BMT to BMT alone (SPACE-2a) and CAS plus BMT to BMT alone (SPACE-2b).

“We originally planned to enroll 3,640 patients; However, the study had to be terminated prematurely due to insufficient recruitment,” the authors write. They report that between July 9, 2009 and December 12, 2019, a total of 513 patients from SPACE-2, SPACE-2a and SPACE-2b were recruited and interviewed, of which 203 (40%) were allocated to CEA plus BMT, 197 (38%) on CAS plus BMT and 113 (22%) on BMT alone. The median follow-up time was 59.6 months.

In your lancet Paper, Reiff, and colleagues report that the cumulative incidence of stroke or death from any cause within 30 days or of an ipsilateral stroke within five years—the study’s primary efficacy endpoint—was 2.5% (95% confidence interval). [CI]1-5.8) with CEA plus BMT, 4.4% (95% CI, 2.2-8.6) with CAS plus BMT, and 3.1% (95% CI, 1-9.4) with BMT alone.

Investigators also report that five strokes and no deaths occurred in both the CEA and CAS groups in the 30 days following the procedure. During the five-year follow-up, three ipsilateral strokes occurred in both the CAS-plus-BMT and BMT-only groups, but none in the CEA-plus-BMT group.

reef et al conclude that CEA plus BMT or CAS plus BMT did not prove superior to BMT alone in terms of risk of stroke or death within 30 days or ipsilateral risk of stroke during the five-year follow-up period. However, they emphasize that their results “should be interpreted with caution” due to the small sample size.

In fact, they note that the study’s small sample size was its “main limitation.” They outline the core of the problem here: “With the small number of observed outcome events, only a few more events would be required to change the outcomes significantly.” pooled analysis can be used and provides data for future meta-analysis in a subject area where only few randomized trials are currently available”.

Randomization is key

In a commentary on the work of Reiff and colleagues, also published in The Lancet Neurology, Alison Halliday (University of Oxford, Oxford, UK) emphasizes the importance of randomized trials in this field of study. Halliday, Principal Investigator of the Asymptomatic Carotid Surgery Trials, notes, “Despite its relatively small sample size, SPACE-2 provides important long-term follow-up data due to the randomized study methodology. Large procedure registries typically discontinue follow-up within days or a few months, and patients treated only with drugs cannot meaningfully be compared without randomization.

“The future of carotid stenosis interventions depends on randomized comparisons of different treatment approaches to ensure bias is minimized while enrolling enough patients. Alternatively, individual patient meta-analysis from similar studies can be used to inform future interventions. SPACE-2 is valuable for future individual patient meta-analysis of these three treatment options.”